X-119851748-C-CTTTTTTTTTTTTTTTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_080632.3(UPF3B):c.263+18_263+19insAAAAAAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0081 ( 85 hom., 63 hem., cov: 0)

Exomes 𝑓: 0.0013 ( 9 hom. 96 hem. )

Failed GnomAD Quality Control

Consequence

UPF3B
NM_080632.3 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0650

Publications

0 publications found

Variant links:

Genes affected

UPF3B (HGNC:20439): (UPF3B regulator of nonsense mediated mRNA decay) This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. The encoded protein is one of two functional homologs to yeast Upf3p. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions. This gene is located on the long arm of chromosome X. Two splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

UPF3B Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability 14
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability with marfanoid habitus
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

UPF3B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant X-119851748-C-CTTTTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1589627.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00815 (523/64175) while in subpopulation AFR AF = 0.0375 (476/12692). AF 95% confidence interval is 0.0347. There are 85 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 85 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3 link	c.263+18_263+19insAAAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 10	ENST00000276201.7	NP_542199.1	Q9BZI7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF3B	ENST00000276201.7 link	c.263+18_263+19insAAAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3		Q9BZI7-1
UPF3B	ENST00000345865.6 link	c.263+18_263+19insAAAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2		Q9BZI7-2

Frequencies

GnomAD3 genomes

AF:

0.00815

AC:

523

AN:

64183

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0375

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00522

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00410

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000377

Gnomad OTH

AF:

0.00644

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00132

AC:

653

AN:

494831

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

AN XY:

145427

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0176

AC:

130

AN:

7373

American (AMR)

AF:

0.00354

AC:

AN:

12137

Ashkenazi Jewish (ASJ)

AF:

0.00105

AC:

AN:

11409

East Asian (EAS)

AF:

0.00206

AC:

AN:

15023

South Asian (SAS)

AF:

0.00470

AC:

134

AN:

28537

European-Finnish (FIN)

AF:

0.000380

AC:

AN:

26344

Middle Eastern (MID)

AF:

0.000632

AC:

AN:

1582

European-Non Finnish (NFE)

AF:

0.000678

AC:

251

AN:

370068

Other (OTH)

AF:

0.00183

AC:

AN:

22358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.357

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00815

AC:

523

AN:

64175

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

AN XY:

11401

show subpopulations

African (AFR)

AF:

0.0375

AC:

476

AN:

12692

American (AMR)

AF:

0.00522

AC:

AN:

4408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2002

East Asian (EAS)

AF:

0.00

AC:

AN:

1437

South Asian (SAS)

AF:

0.00415

AC:

AN:

965

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000377

AC:

AN:

39748

Other (OTH)

AF:

0.00636

AC:

AN:

786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

585

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability 14

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.065

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-119851748-C-CTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over